Our study shows that (a) EMAST formation is dependent on the MMR background, with hMSH3-deficiency matching complete MMR-deficiency in causing EMAST, (b) hMSH3-deficiency mutation rates for EMAST formation are markedly higher compared to that of hMSH6-deficiency (essentially null for EMAST formation), (c) knockdown of hMSH3 alone initiates formation of EMAST, and (d) oxidative stress may be one of the factors causing deficiency of hMSH3, as this MMR protein shifts its subcellular location with H2O2. Here, MSH3 is linked to hyperinsulinemic hypoglycemia, familial, 4.